Is cell transplantation safe for ischemic heart disease? Studies of multiple modalities of cell transplantation for ischemic heart disease have shown improvement in cardiac function in patients with ischemic heart disease. Subepicardial intramyocardial injection is the most direct and reliable, facilitating postoperative cell differentiation identification, but it may be difficult for some patients with advanced heart failure due to the need for open-heart surgery, and has side effects such as inducing arrhythmias and causing cell leakage back; subendocardial intramyocardial injection has the advantage of not requiring open-heart surgery, but requires considerable cardiovascular interventional techniques, and the injection location is difficult to fix, with the potential risk of causing Intracoronary injection is more direct and less traumatic, and is the most commonly used transplantation method, but it requires a high concentration of cells and must be done under interventional procedures. The transvenous route is nearly noninvasive, but a large number of cells may migrate to other organs with blood flow, causing unnecessary revascularization of distant organs, which may lead to complications such as hemangiomas and retinal vascular proliferation. Most patients with ischemic heart disease have undergone coronary intervention along with bone marrow stem cell transplantation, and the effect of cell therapy on restenosis after intervention has been a focus of attention. Therefore, although bone marrow stem cell transplantation offers hope for the treatment of patients with end-stage heart failure, the safety of stem cell therapy has also been widely questioned. 1. Restenosis Wen Shang-yu et al. used small pigs to prepare a myocardial infarction model and explored the effect of bone marrow single nucleated cell transplantation on in-stent restenosis of coronary arteries. They concluded that bone marrow single nucleus stem cell transplantation did not increase the incidence of in-stent restenosis after coronary intervention in a small porcine myocardial ischemia model. Chen et al. applied percutaneous transluminal coronary angioplasty catheter to dilate the rat thoracoabdominal aorta to create an arterial injury model, and injected bone marrow MSCs into the rat aorta. They found that bone marrow MSCs transplanted through the aorta could homing to the severely damaged aortic intima and differentiated into smooth muscle-like cells, which participated in the formation of new intima and aggravated the restenosis after angioplasty in rats. Tendera et al. used autologous bone marrow and peripheral progenitor cells transplanted via coronary arteries in patients with acute myocardial infarction and found no associated restenosis. Boyle et al. treated patients with chronic ischemic heart disease by mobilizing bone marrow stem cells with G-CSF and transplanting them into coronary arteries, and also found no associated in-stent restenosis. In contrast, Steinwender et al. found a significant increase in the incidence of in-stent restenosis and reinfarction after 6 months of follow-up with coronary transplantation of mobilized peripheral blood stem cells in patients with acute myocardial infarction after successful PCI, and Bartunek et al. found an increase in coronary events including in-stent re-occlusion, restenosis, and in situ lesions after intracoronary transplantation of CD133-positive bone marrow progenitor cells. Thus animal experiments and clinical studies have shown different results, what are the specific causes and mechanisms for the occurrence of restenosis? are still unclear. 2. Arrhythmias Arrhythmias induced by cell transplantation are mostly seen in skeletal muscle stem cell transplantation and are mostly caused by transendocardial or epicardial injection, and no arrhythmias have been reported in transcoronary transplantation. Skeletal muscle stem cells transplanted with myotubes are highly developed, have abnormally active contractility, and are not host cell dependent. There is no connection between myocytes, while the connection between host cardiomyocytes is instead strengthened, and the contraction of myogenic stem cells cannot be transmitted to the surrounding host cardiomyocytes. The electrical signal from the myotubes excites a slow voltage-dependent discharge in a double pulse, resembling the control of nerves rather than the action of the cells themselves. Embryonic stem cells have a coherent action potential and contraction with a lower conduction rate than normal cardiac myocytes. The presence of connexin45 and the heterogeneity of ion channels early in development will lead to slow conduction in the myocardium, resulting in foldback arrhythmias. Membrane clamp studies in isolates have confirmed the presence of multiple types of action potentials in embryonic stem cells with reduced maximum frontal potential velocity, prolonged inhibition periods, and spontaneous electrical activity in culture. It is suggested that these stem cells can trigger arrhythmias from three different mechanisms i.e. folding, autoregulation and triggering mechanisms. It was found that injection of bone marrow MSCs into post-infarct pig hearts increased ventricular sympathetic nerve density, thereby increasing contractility and ejection fraction, but also predisposed to ventricular arrhythmias; bone marrow stem cells in the infarct area during differentiation had not only morphological characteristics of their own cardiomyocytes but also electrophysiological characteristics of embryonic cardiomyocytes, suggesting that the regenerated myocardium had arrhythmogenic effects. arrhythmogenic effect of the regenerated myocardium. However, unlike skeletal muscle stem cells, there have been few reports to date of malignant arrhythmias in humans or animals after autologous bone marrow MSCs. 3, Adverse reactions of peripheral blood stem cell mobilization, isolation, collection and transfusion The overall incidence of adverse reactions in peripheral blood stem cell (PBSC) mobilization, isolation, collection and transfusion was 71.4%, including 37.1% of adverse reactions during PBSC mobilization and 15.3% of adverse reactions during PBSC isolation and collection, including 8.6% of hypocalcemic perioral numbness and 5.6% of angina pectoris. The incidence of adverse reactions during PBSC infusion via coronary return was 20.0%, including sinus bradycardia (2.9%), sinus arrest + III degree AV block + hypotension (2.9%), ventricular fibrillation (2.9%), and blood pressure drop (11.4%). Despite the high incidence of adverse reactions in this method for acute myocardial infarction, all of these adverse reactions improved after discontinuation and symptomatic treatment, and no uncorrectable adverse reactions occurred; no fatal cases occurred. In addition, they also reported other adverse reactions, such as: bone pain, hypothermia, rash, weakness, splenic embolism and heart failure or angina pectoris aggravation. 4. other adverse events Gao Lianru et al. found that some patients had chills and fever during transcoronary transplantation, and after treatment the patient’s temperature decreased. george et al. showed that transplantation of splenic cell-derived endothelial progenitor cells (EPCs) and bone marrow cells in the apoE-/- mouse model accelerated the formation of atherosclerosis and reduced plaque stability-related markers Yoon et al. observed that intracoronary injection of bone marrow cells in a rat model caused calcification within the myocardium showing that the injected cells were directly involved in the process, and their study is consistent with the findings of Sata et al. which showed that bone marrow-derived cells formed a large number of smooth muscle cells associated with the constituent atherosclerotic cells in an experimental model. Intracoronary transplantation of bone marrow mesenchymal stem cells caused acute myocardial ischemia and subacute myocardial microinfarction, and it has also been reported that bone marrow mononuclear cells in culture in vitro can spontaneously exhibit a tendency to proliferate rapidly, and that injection of this cell population into animals can further transform into cells with malignant properties. However, there are no clinical reports of tumor initiation. Therefore, most studies so far have shown that stem cell transplantation is safe.